Serotonin is a ubiquitous neurotransmitter in the brain that has been linked to the pathophysiology of avariety of mental disorders. As such, there is great interest in understanding the cellular and molecular mechanisms by which serotonin regulates neuronal functionin the brain. Serotonin acts in the brain through 7 different families of serotonin receptors. Therefore, understanding the physiological function of different serotonin receptor subtypes is an important step in trying to understand how serotonin works in the brain. The long term goal of this project is to understand the physiological role of different serotonin receptor subtypes, and the cellular and molecular mechanisms that underlie these effects. During previous funding periods we have focused on several distinct classes of receptors including 5-HT1A, 5-HT4 and 5-HT7 receptors. In the present application we propose to expand these studies to receptors of the 5-HT2A subtype. These receptors are particularly interesting because they have been identified as the targets for classic hallucinogens, such as LSD, and may participate in the pathophysiology of schizophrenia and depression, For the present project we propose to combine electrophysiological and molecular biological approaches to understand how 5-HT2A receptors regulate neuronal function in the rat prefrontal cortex. In a first Specific Aim we propose to examine mechanistically how activation of 5-HT2A receptors increase glutamate synaptic transmission in this region. In the second Specific Aim we will test the idea that one important effect of serotonin receptors is to regulate synaptic plasticity in prefrontal cortex. Finally, in a third Specific Aim, we will test the hypothesis that scaffolding proteins, and specifically MUPP1, play an important role in organizing signaling by 5-HT2A receptor in the brain.Combined, these three Specific Aims will begin to fill some of the gaps in our understanding of what 5-HT2A receptors do, and how they do it, in the cerebral cortex. As such, these studies should contribute to our understanding of the biological basis underlying mental disorders. Equally important, we hope these studies will also contribute to the development on novel therapeuric approaches for the treatment of these disorders.